Method for separating methyl 4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoro-2-pyridinyl)-6-methyl-1,4-dihydro-5-pyrimidine-carboxylate-racemate

ABSTRACT

The enantiomers of methyl 4-(2-chloro-4-fluorphenyl)-2-(3,5-difluoro-2-pyridinyl)-6-methyl-1,4-dihydro-5-pyrimidinecarhoxylate can be separated with the aid of (−)-camphanic acid.

[0001] The invention relates to a method for separating the enantiomericmethyl4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoro-2-pyridinyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxylateswith the aid of (−)-camphanic acid.

[0002] The compound methyl4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoro-2-pyridinyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxylatecorresponds to the formula

[0003] It is able to act as HBV core protein inhibitor and is suitablefor the prophylaxis and treatment of hepatitis, especially hepatitis B.The compound and various methods for preparing it are disclosed in EP-A1 080 086 (example 61). The preferred optically active form is the(−)-enantiomer. The enantiomers can be separated on chiral columns.Although this method leads to good results, its suitability forindustrial production is low.

[0004] It has now been found that the two enantiomeric methyl4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoro-2-pyridinyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxylatescan be separated via their diastereomeric (−)-camphanic salts; this isbecause the (−)-camphanic salt of the (R) enantiomer is less solublethan the (−)-camphanic salt of the (L) enantiomer in many solvents. Theterm “salts” also includes for the purposes of this inventioncocrystallized products; according to the NMR spectrum, the base ispresent mainly in unprotonated form.

[0005] The invention therefore relates to a method for separating theenantiomeric methyl4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoro-2-pyridinyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxylateswith the aid of (−)-camphanic acid.

[0006] The difference in solubility of the diastereomeric salts can beutilized in principle for two different types of separation thereof:firstly by (fractional) crystallization of the less soluble diastereomerfrom solution or secondly by dissolving the more soluble diastereomerout of the mixture of the solid diastereomers.

[0007] The procedure is thus usually such that (−)-camphanic acid andthe racemate to be separated are reacted to give the correspondingdiastereomeric salts and either a) the reaction product is dissolved andthe less soluble product is induced to precipitate by cooling thesolution and/or partially stripping off the solvent, and theprecipitated product is separated from the solution or b) the solidreaction product is treated with solvent in order to dissolve the moresoluble product and to separate this solution from the less solubleresidue.

[0008] The term “solvent” includes for the purposes of the invention allconventional solvents, e.g. hydrocarbons such as benzene, xylene,toluene, hexane, cyclohexane or petroleum fractions, halohydrocarbonssuch as dichloromethane, trichloromethane, tetrachloromethane,trichloroethane, tetrachloroethane, 1,2-dichloroethane ortrichloroethylene, alcohols such as methanol, ethanol, n-propanol,isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether,methyl isopropyl ether, diisopropyl ether, glycol monomethyl ether,glycol dimethyl ether, diethylene glycol dimethyl ether,tetrahydrofuran, dioxane, ketones such as acetone, methyl ethyl ketone,carboxylic acids such as glacial acetic acid, esters such as ethylacetate and butyl acetate, heterocycles such as pyridine or aproticsolvents such as nitromethane, acetonitrile, dimethylformamide, dimethylsulfoxide and hexamethylphosphoric triamide and mixtures of saidcompounds. It is also possible where appropriate to add water towater-miscible organic solvents. Preferred solvents for the reaction ofthe racemate to be separated with (−)-camphanic acid are alcohols,especially ethanol; preferred solvents for separating the diastereomericsalts are ethers, esters and ketones, especially diisopropyl ether.

[0009] The dissolving of the diastereomer can take place within a widetemperature range; preferably at the boiling point of the solvent downto 20° C. The temperatures during the crystallization of the lesssoluble diastereomerically pure salt or during the washing out of themore soluble diastereomerically pure salt can also lie within a widerange; it is preferably −40 to 20° C., preferably about 0° C.

[0010] The liberation of the free enantiomer from the diastereomericallypure salt can take place with any conventional base such as ammonia,alkali metal hydroxides such as sodium or potassium hydroxide, alkalimetal carbonates or bicarbonates such as sodium or potassium carbonateor bicarbonate. The pure enantiomer can then be extracted from the basicaqueous solution directly with an organic solvent.

[0011] The (−)-camphanic acid can be precipitated by acidifying theaqueous solution thereof and then be reused.

[0012] The invention further relates to D- and L-methyl4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoro-2-pyridinyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxylate(−)-camphanic acid salt.

EXAMPLE Racemate Resolution with (−)-Camphanic Acid

[0013] (−)-Methyl(4R)-4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoro-2-pyridinyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxylate

[0014] 37.68 g (95.21 mmol) of methyl4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoro-2-pyridinyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxylateand 18.87 g (95.21 mmol) of (−)-camphanic acid were dissolved in boilingethanol. After cooling, the ethanol was evaporated off to dryness; theresidue was broken up, mixed with diisopropyl ether and heated to thereflux temperature. After cooling to 0° C. and standing overnight, thecrystals were filtered off with suction and washed with cold diisopropylether. The filter cake was suspended in ethyl acetate, made alkalinewith 10% by weight aqueous sodium carbonate solution and extracted twicewith ethyl acetate. The organic phases were dried with sodium sulfateand evaporated. The residue was crystallized with a little cold ethanol.17.7 g (93.7%) of methyl4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoro-2-pyridinyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxylate(ee 97%, HPLC) were obtained.

[0015] The absolute configuration (R) was determined by x-rayinvestigation.

1. A method for resolving a mixture of the enantiomers of methyl4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoro-2-pyridinyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxylatecomprising the steps of adding (−)-camphanic acid to form a mixture ofdiastereomeric (−)-camphanic salts, and separating said salts.
 2. Themethod as claimed in claim 1, wherein the (−)-camphanic acid salts of(D/L)-methyl4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoro-2-pyridinyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxylateare separated by crystallization, and each enantiomer is liberated withbase, and isolated where appropriate, from the removed solid(−)-camphanic acid salt and/or from the removed solution.
 3. The methodas claimed in claim 1, wherein the more soluble diastereomer isdissolved out of the mixture of the (−)-camphanic acid salts of(D/L)-methyl4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoro-2-pyridinyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxylate,the resulting solution is separated from the less soluble diastereomer,and each enantiomer is liberated with base, and isolated whereappropriate, from the removed solid (−)-camphanic acid salt and/or fromthe removed solution.
 4. D-Methyl4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoro-2-pyridinyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxylate(−)-camphanic acid salt.
 5. L-Methyl4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoro-2-pyridinyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxylate(−)-camphanic acid salt.